The role of the myosin ATPase activity in adaptive thermogenesis by skeletal muscle.

Cooke R - Biophys Rev (2011)

Bottom Line:
Modulation of the population of this state, relative to the normal relaxed state, was proposed to be a major contributor to adaptive thermogenesis in resting muscle.In particular, thermogenesis by myosin has been proposed to play a role in the dissipation of calories during overfeeding.Up-regulation of muscle thermogenesis by pharmaceuticals that target the SRX would provide new approaches to the treatment of obesity or high blood sugar levels.

ABSTRACTResting skeletal muscle is a major contributor to adaptive thermogenesis, i.e., the thermogenesis that changes in response to exposure to cold or to overfeeding. The identification of the "furnace" that is responsible for increased heat generation in resting muscle has been the subject of a number of investigations. A new state of myosin, the super relaxed state (SRX), with a very slow ATP turnover rate has recently been observed in skeletal muscle (Stewart et al. in Proc Natl Acad Sci USA 107:430-435, 2010). Inhibition of the myosin ATPase activity in the SRX was suggested to be caused by binding of the myosin head to the core of the thick filament in a structural motif identified earlier by electron microscopy. To be compatible with the basal metabolic rate observed in vivo for resting muscle, most myosin heads would have to be in the SRX. Modulation of the population of this state, relative to the normal relaxed state, was proposed to be a major contributor to adaptive thermogenesis in resting muscle. Transfer of only 20% of myosin heads from the SRX into the normal relaxed state would cause muscle thermogenesis to double. Phosphorylation of the myosin regulatory light chain was shown to transfer myosin heads from the SRX into the relaxed state, which would increase thermogenesis. In particular, thermogenesis by myosin has been proposed to play a role in the dissipation of calories during overfeeding. Up-regulation of muscle thermogenesis by pharmaceuticals that target the SRX would provide new approaches to the treatment of obesity or high blood sugar levels.

Fig5: Components of energy use in the human body. Energy intake in the diet for an average adult human in our modern society (i.e. not engaged in intense physical activity) is approximately 8 MJ day−1. Approximately two-thirds of this energy is required for obligatory cellular functions. A variable amount is used to power physical activity. Adaptive thermogenesis, responding to exposure to cold and to nutritional state, is highly variable and typically amounts to around 25% of the total. The difference between energy intake and energy used by the factors listed above is either stored to—or retrieved from—lipids, proteins and glycogen.

Mentions:
Whole body energy intake can be broken down into several components (Fig. 5; for review, see Johannsen and Ravussin 2008; Levine 2004; Lowell and Spiegelman 2000; Wijers et al. 2009). An average adult human in our modern society (i.e. not engaged in intense physical activity) consumes approximately 8 MJ day−1. Approximately two-thirds of this energy is used to fuel basic cellular functions, composed of the many exothermic cellular processes required for cell homeostasis, such as protein synthesis, ion pumping, cell division, etc. This component, known as the basal metabolic rate (BMR), does not change by a significant amount. Resting skeletal muscle has a low metabolic rate per unit volume, approximately 0.7 W kg−1 in rabbit muscle and 0.5 W kg−1 in human muscle. Although these rates are lower than those of many other tissues, such as brain or liver, skeletal muscle contributes about 25% of the obligatory thermogenesis due its large mass (Zurlo et al. 1990). A proportion of the energy taken in is expended by muscular activity. This component can vary widely depending on one’s lifestyle, and for people not involved in manual labor typically amounts to approximately 15–25% of the total (Levine 2004). There is a component of energy use, known as adaptive thermogenesis, which is altered by conditions, such as cold exposure and the ingestion of excess calories. The difference between the energy taken in and that used by the metabolic components given above is made up for by the storage or consumption of fat and, to a lesser extent, of protein and glycogen. Because the BMR does not change significantly, adaptive thermogenesis and activity both play an important role in maintaining body weight. This review will concentrate on thermogenesis by resting skeletal muscle, its role in adaptive thermogenesis and, in particular, on the question of what is the furnace within the muscle responsible for producing the heat. Our group has recently proposed a new mechanism for producing heat in resting muscle, discussed above, and this model will be integrated into the existing physiological data on adaptive thermogenesis and whole body metabolism.Fig. 5

Fig5: Components of energy use in the human body. Energy intake in the diet for an average adult human in our modern society (i.e. not engaged in intense physical activity) is approximately 8 MJ day−1. Approximately two-thirds of this energy is required for obligatory cellular functions. A variable amount is used to power physical activity. Adaptive thermogenesis, responding to exposure to cold and to nutritional state, is highly variable and typically amounts to around 25% of the total. The difference between energy intake and energy used by the factors listed above is either stored to—or retrieved from—lipids, proteins and glycogen.

Mentions:
Whole body energy intake can be broken down into several components (Fig. 5; for review, see Johannsen and Ravussin 2008; Levine 2004; Lowell and Spiegelman 2000; Wijers et al. 2009). An average adult human in our modern society (i.e. not engaged in intense physical activity) consumes approximately 8 MJ day−1. Approximately two-thirds of this energy is used to fuel basic cellular functions, composed of the many exothermic cellular processes required for cell homeostasis, such as protein synthesis, ion pumping, cell division, etc. This component, known as the basal metabolic rate (BMR), does not change by a significant amount. Resting skeletal muscle has a low metabolic rate per unit volume, approximately 0.7 W kg−1 in rabbit muscle and 0.5 W kg−1 in human muscle. Although these rates are lower than those of many other tissues, such as brain or liver, skeletal muscle contributes about 25% of the obligatory thermogenesis due its large mass (Zurlo et al. 1990). A proportion of the energy taken in is expended by muscular activity. This component can vary widely depending on one’s lifestyle, and for people not involved in manual labor typically amounts to approximately 15–25% of the total (Levine 2004). There is a component of energy use, known as adaptive thermogenesis, which is altered by conditions, such as cold exposure and the ingestion of excess calories. The difference between the energy taken in and that used by the metabolic components given above is made up for by the storage or consumption of fat and, to a lesser extent, of protein and glycogen. Because the BMR does not change significantly, adaptive thermogenesis and activity both play an important role in maintaining body weight. This review will concentrate on thermogenesis by resting skeletal muscle, its role in adaptive thermogenesis and, in particular, on the question of what is the furnace within the muscle responsible for producing the heat. Our group has recently proposed a new mechanism for producing heat in resting muscle, discussed above, and this model will be integrated into the existing physiological data on adaptive thermogenesis and whole body metabolism.Fig. 5

Bottom Line:
Modulation of the population of this state, relative to the normal relaxed state, was proposed to be a major contributor to adaptive thermogenesis in resting muscle.In particular, thermogenesis by myosin has been proposed to play a role in the dissipation of calories during overfeeding.Up-regulation of muscle thermogenesis by pharmaceuticals that target the SRX would provide new approaches to the treatment of obesity or high blood sugar levels.

ABSTRACTResting skeletal muscle is a major contributor to adaptive thermogenesis, i.e., the thermogenesis that changes in response to exposure to cold or to overfeeding. The identification of the "furnace" that is responsible for increased heat generation in resting muscle has been the subject of a number of investigations. A new state of myosin, the super relaxed state (SRX), with a very slow ATP turnover rate has recently been observed in skeletal muscle (Stewart et al. in Proc Natl Acad Sci USA 107:430-435, 2010). Inhibition of the myosin ATPase activity in the SRX was suggested to be caused by binding of the myosin head to the core of the thick filament in a structural motif identified earlier by electron microscopy. To be compatible with the basal metabolic rate observed in vivo for resting muscle, most myosin heads would have to be in the SRX. Modulation of the population of this state, relative to the normal relaxed state, was proposed to be a major contributor to adaptive thermogenesis in resting muscle. Transfer of only 20% of myosin heads from the SRX into the normal relaxed state would cause muscle thermogenesis to double. Phosphorylation of the myosin regulatory light chain was shown to transfer myosin heads from the SRX into the relaxed state, which would increase thermogenesis. In particular, thermogenesis by myosin has been proposed to play a role in the dissipation of calories during overfeeding. Up-regulation of muscle thermogenesis by pharmaceuticals that target the SRX would provide new approaches to the treatment of obesity or high blood sugar levels.